RT Journal Article SR Electronic T1 Human APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6771 OP 6779 DO 10.1523/JNEUROSCI.0887-09.2009 VO 29 IS 21 A1 Kelly R. Bales A1 Feng Liu A1 Su Wu A1 Suizhen Lin A1 Deanna Koger A1 Cynthia DeLong A1 Jeffrey C. Hansen A1 Patrick M. Sullivan A1 Steven M. Paul YR 2009 UL http://www.jneurosci.org/content/29/21/6771.abstract AB To investigate the role of human apolipoprotein E (apoE) on Aβ deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and Aβ peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain Aβ and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain Aβ deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of Aβ42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain Aβ burden, and the majority of apoE was associated with Aβ. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 < E3 ≪ E2), resulting in early and dramatic apoE isoform-dependent effects on brain Aβ levels (E4 ≫ E3 > E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.